Each year, outbreaks of seasonal influenza produce substantial morbidity, mortality and attendant economic costs in the United States. Household transmission has been proposed as a major driver of influenza epidemics, and circulation of other respiratory viruses. The overall objective of this application is to expand our understanding of acute respiratory illness risk, susceptibility, and transmission through continuation of our established household cohort study. We have identified the frequency of detection and co-detection of 13 respiratory viruses, and demonstrated lower vaccine effectiveness and reduced response to current season vaccination among those vaccinated in the prior year. Our long term goal is to further employ the established household platform for the surveillance of both currently recognized and emerging respiratory viruses (e.g. enterovirus D68) using innovative laboratory and statistical methods. Of particular interest will be the evaluation of determinants o protection produced by past influenza infection and vaccination. We will accomplish the overall objectives through the following specific aims: Aim 1) To characterize the effect of recent infection and vaccination history on the risk of subsequent influenza infection; Aim 2) To expand previous evaluations of immune correlates of protection and of susceptibility to influenza using assays measuring antibodies to the hemagglutinin (HA) and neuraminidase (NA) antigens plus additional, novel assays in development; Aim 3) To estimate household infection parameters and factors affecting transmission in households where influenza has been introduced. Enrolling and following individual households for up to five years allows for the investigation of risk factos and immune correlates as they impact influenza transmission patterns over a multiple year span. This study will address major gaps in our understanding of correlates of protection and the transmission of influenza and other respiratory viruses in the following ways: the proposed work will (1) define the contributions of vaccination and infection history to risk of subsequent respiratory infection, and inform the development of improved vaccines against influenza and other respiratory viruses (e.g. RSV), (2) identify key immune correlates which will serve as targets for future research to reduce vaccine failures in the general population and (3) provide robust estimates of influenza transmission patterns in households and communities to inform public health intervention efforts. Our results will lead to improvements in the understanding and prevention of respiratory virus infection in U.S. communities.